`
`FANAPT®
`(iloperidone) Tablets
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`These highlights do not include all the information needed to use FANAPT
`safely and effectively. See full prescribing information for FANAPT.
`FANAPT® (iloperidone) tablets
`Initial U.S. Approval: 2009
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA­
`RELATED PSYCHOSIS
`
`
`See full prescribing information for complete boxed warning.
`Elderly patients with dementia-related psychosis treated with antipsychotic
`
`drugs are at an increased risk of death. FANAPT is not approved for use in
`
`patients with dementia-related psychosis. (5.1)
`
`______________________
`______________________
`INDICATIONS AND USAGE
`FANAPT is an atypical antipsychotic agent indicated for the treatment of schizophrenia
`
`in adults.(1) Efficacy was established in two short-term (4-and 6-week) placebo-and
`
`active-controlled studies of adult patients with schizophrenia.(14) In choosing among
`
`treatments, prescribers should consider the ability of FANAPT to prolong the QT
`
`interval and the use of other drugs first. Prescribers should also consider the need to
`
`
`titrate FANAPT slowly to avoid orthostatic hypotension, which may lead to delayed
`
`effectiveness compared to some other drugs that do not require similar titration.
`
` ____________________
`___________________
`DOSAGE AND ADMINISTRATION
`The recommended target dosage of FANAPT tablets is 12 to 24 mg/day administered
`
`twice daily. This target dosage range is achieved by daily dosage adjustments, alerting
`
`patients to symptoms of orthostatic hypotension, starting at a dose of 1 mg twice daily,
`
`then moving to 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg twice daily on days 2, 3, 4,
`
`5, 6, and 7 respectively, to reach the 12 mg/day to 24 mg/day dose range. FANAPT
`
`can be administered without regard to meals. (2.1)
`DOSAGE FORMS AND STRENGTHS __________________
`__________________
`1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and 12 mg tablets. (3)
`
`________________________ CONTRAINDICATIONS________________________
`
`Known hypersensitivity to FANAPT or to any components in the formulation. (4)
`
`____________________
`___________________
`WARNINGS AND PRECAUTIONS
`Elderly patients with dementia-related psychosis who are treated with
`
`
`
`
`•
`atypical antipsychotic drugs are at an increased risk of death and
`cerebrovascular-related adverse events, including stroke. (5.1)
`
`QT prolongation: Prolongs QT interval and may be associated with
`
`arrhythmia and sudden death—consider using other antipsychotics first.
`
`Avoid use of FANAPT in combination with other drugs that are known to
`
`
`prolong QTc; use caution and consider dose modification when
`prescribing FANAPT with other drugs that inhibit FANAPT metabolism.
`Monitor serum potassium and magnesium in patients at risk for electrolyte
`
`
`disturbances. (1, 5.2, 7.1, 7.3, 12.3)
`
`
`
`
`•
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-
`RELATED PSYCHOSIS
`INDICATIONS AND USAGE
`DOSAGE AND ADMINISTRATION
`2.1
`Usual Dose
`Dosage in Special Populations
`2.2
`2.3 Maintenance Treatment
`
`
`2.4
`Reinitiation of Treatment in Patients Previously Discontinued
`
`
`2.5
`Switching from Other Antipsychotics
`
`DOSAGE FORMS AND STRENGTHS
`CONTRAINDICATIONS
`WARNINGS AND PRECAUTIONS
`5.1
`Increased Risks in Elderly Patients with Dementia-Related Psychosis
`
`5.2
`QT Prolongation
`5.3
`Neuroleptic Malignant Syndrome (NMS)
`Tardive Dyskinesia
`5.4
`
`Hyperglycemia and Diabetes Mellitus
`5.5
`5.6 Weight Gain
`
`5.7
`Seizures
`
`5.8
`Orthostatic Hypotension and Syncope
`5.9
`Leukopenia, Neutropenia and Agranulocytosis
`5.10 Hyperprolactinemia
`5.11 Body Temperature Regulation
`5.12 Dysphagia
`5.13 Suicide
`5.14 Priapism
`
`1
`2
`
`3
`4
`5
`
`
`
`Reference ID: 2921042
`
`
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`
`•
`
`•
`
`
`•
`
`Neuroleptic Malignant Syndrome: Manage with immediate discontinuation
`
`of drug and close monitoring. (5.3)
`
`Tardive dyskinesia: Discontinue if clinically appropriate. (5.4)
`
`
`Hyperglycemia and diabetes mellitus: Monitor glucose regularly in patients
`
`at risk for diabetes. (5.5)
`
`Seizures: Use cautiously in patients with a history of seizures or with
`
`
`conditions that lower seizure threshold. (5.7)
`Orthostatic hypotension: Dizziness, tachycardia, and syncope can occur
`with standing. (5.8)
`Leukopenia, Neutropenia, and Agranulocytosis have been reported with
`
`antipsychotics. Patients with a pre-existing low white blood cell count
`
`(WBC) or a history of leukopenia/neutropenia should have their complete
`
`blood count (CBC) monitored frequently during the first few months of
`
`therapy and should discontinue FANAPT at the first sign of a decline in
`
`WBC in the absence of other causative factors. (5.9)
`Suicide: Close supervision of high risk patients. (5.13)
`Priapism: Cases have been reported in association with FANAPT
`
`treatment. (5.14)
`Potential for cognitive and motor impairment: Use caution when operating
`machinery. (5.15)
`for additional WARNINGS and
`Information
`See Full Prescribing
`
`•
`
`PRECAUTIONS.
`________________________ADVERSE REACTIONS________________________
`
`Commonly observed adverse reactions (incidence ≥5% and two-fold greater than
`
`fatigue, nasal congestion, orthostatic
`placebo) were: dizziness, dry mouth,
`
`hypotension, somnolence, tachycardia, and weight increased. (6.1)
`To report SUSPECTED ADVERSE REACTIONS, contact Vanda Pharmaceuticals
`1-800-FDA-1088 or
`at
`1-888-49VANDA
`(1-888-498-2632) or FDA
`at
`
`www.fda.gov/medwatch.
`________________________ DRUG INTERACTIONS ________________________
`
`The dose of FANAPT should be reduced in patients co-administered a
`
`
`•
`strong CYP2D6 or CYP3A4 inhibitor. (2.2, 7.1)
`
`___________________
`___________________
`USE IN SPECIFIC POPULATIONS
`Pregnancy: No human or animal data. Use only if clearly needed. (8.1)
`
`•
`Nursing Mothers: Should not breast feed. (8.3)
`
`•
`Pediatric Use: Safety and effectiveness not established in children and
`
`
`•
`adolescents. (8.4)
`Hepatic
`Impairment: Not
`impairment. (8.7)
`The dose of FANAPT should be reduced in patients who are poor
`metabolizers of CYP2D6. (12.3)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`•
`
`
`•
`
`recommended
`
`for patients with hepatic
`
`
`Revised: 3/2011
`
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`12
`
`5.15 Potential for Cognitive and Motor Impairment
`
`ADVERSE REACTIONS
`6.1
`Clinical Studies Experience
`DRUG INTERACTIONS
`7.1
`Potential for Other Drugs to Affect FANAPT
`
`
`7.2
`Potential for FANAPT to Affect Other Drugs
`
`
`7.3
`Drugs that Prolong the QT Interval
`USE IN SPECIFIC POPULATIONS
`8.1
`Pregnancy
`8.2
`Labor and Delivery
`8.3
`Nursing Mothers
`8.4
`Pediatric Use
`Geriatric Use
`8.5
`
`Renal Impairment
`8.6
`
`Hepatic Impairment
`8.7
`
`8.8
`Smoking Status
`DRUG ABUSE AND DEPENDENCE
`9.1
`Controlled Substance
`9.2
`Abuse
`OVERDOSAGE
`10.1 Human Experience
`10.2 Management of Overdose
`DESCRIPTION
`CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`
`
`
`

`

`
`13
`
`14
`16
`17
`
`NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`CLINICAL STUDIES
`HOW SUPPLIED/STORAGE AND HANDLING
`PATIENT COUNSELING INFORMATION
`17.1 QT Interval Prolongation
`17.2 Neuroleptic Malignant Syndrome
`
`17.3 Orthostatic Hypotension
`
`
`
`
` FULL PRESCRIBING INFORMATION
`
`
`Interference with Cognitive and Motor Performance
`17.4
`17.5 Pregnancy
`17.6 Nursing
`17.7 Concomitant Medication
`
`17.8 Alcohol
`17.9 Heat Exposure and Dehydration
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
`
`INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED
`WARNING:
`
`PSYCHOSIS
`Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
`increased risk of death. Analysis of seventeen placebo-controlled trials (modal duration 10
`weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in
`the drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated
`patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-
` treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
`
`Although the causes of death were varied, most of the deaths appeared to be either
`cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
`Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with
`conventional antipsychotic drugs may increase mortality. The extent to which the findings
`of increased mortality in observational studies may be attributed to the antipsychotic drug
`
`as opposed to some characteristic(s) of the patients is not clear. FANAPT is not approved
`
`for the treatment of patients with Dementia-Related Psychosis. [see Warnings and
`
`Precautions (5.1)]
`
`
`
`INDICATIONS AND USAGE
`1
`FANAPT® tablets are indicated for the treatment of adults with schizophrenia. Efficacy was
`
`
` established in two short-term (4-and 6-week) placebo-and active-controlled studies of adult
`patients with schizophrenia [see Clinical Studies (14)].
`When deciding among the alternative treatments available for this condition, the prescriber should
`
`consider the finding that FANAPT is associated with prolongation of the QTc interval [see Warnings
`and Precautions (5.2)]. Prolongation of the QTc interval is associated in some other drugs with the
`ability to cause torsade de pointes-type arrhythmia, a potentially fatal polymorphic ventricular
`
`tachycardia which can result in sudden death. In many cases this would lead to the conclusion that
`
`other drugs should be tried first. Whether FANAPT will cause torsade de pointes or increase the
`rate of sudden death is not yet known.
`
`Patients must be titrated to an effective dose of FANAPT. Thus, control of symptoms may be
`delayed during the first 1 to 2 weeks of treatment compared to some other antipsychotic drugs that
`do not require a similar titration. Prescribers should be mindful of this delay when selecting an
`antipsychotic drug for the treatment of schizophrenia [see Dosage and Administration (2.1) and
`Clinical Studies (14)].
`
`Reference ID: 2921042
`
`
`
`

`

`
`
`The effectiveness of FANAPT in long-term use, that is, for more than 6 weeks, has not been
`systematically evaluated in controlled trials. Therefore, the physician who elects to use FANAPT
`for extended periods should periodically re-evaluate the long-term usefulness of the drug for the
`
`individual patient [see Dosage and Administration (2.3)].
`
`
`2
`
`DOSAGE AND ADMINISTRATION
`
`Usual Dose
`2.1
`
`FANAPT must be titrated slowly from a low starting dose to avoid orthostatic hypotension due to its
`alpha-adrenergic blocking properties. The recommended starting dose for FANAPT tablets is 1 mg
`twice daily. Increases to reach the target dose range of 6-12 mg twice daily may be made with
`daily dosage adjustments to 2 mg twice daily, 4 mg twice daily, 6 mg twice daily, 8 mg twice daily,
`
`10 mg twice daily, and 12 mg twice daily on days 2, 3, 4, 5, 6, and 7, respectively. Efficacy was
`
`demonstrated with FANAPT in a dose range of 6 to 12 mg twice daily. Prescribers should be
`mindful of the fact that patients need to be titrated to an effective dose of FANAPT. Thus, control of
`symptoms may be delayed during the first 1 to 2 weeks of treatment compared to some other
`antipsychotic drugs that do not require similar titration. Prescribers should also be aware that
`some adverse effects associated with FANAPT use are dose related.
`The maximum recommended dose is 12 mg twice daily (24 mg/day); FANAPT doses above 24
`
`mg/day have not been systematically evaluated in the clinical trials.
`
`FANAPT can be administered without regard to meals.
`
`Dosage in Special Populations
`2.2
`Dosage adjustments are not routinely indicated on the basis of age, gender, race, or renal
`impairment status [see Use in Specific Populations (8.6, 8.7)].
`Dosage adjustment for patients taking FANAPT concomitantly with potential CYP2D6
`inhibitors: FANAPT dose should be reduced by one-half when administered concomitantly with
`strong CYP2D6 inhibitors such as fluoxetine or paroxetine. When the CYP2D6 inhibitor is
`withdrawn from the combination therapy, FANAPT dose should then be increased to where it was
`before [see Drug Interactions (7.1)].
`Dosage adjustment for patients taking FANAPT concomitantly with potential CYP3A4
`inhibitors: FANAPT dose should be reduced by one-half when administered concomitantly with
`strong CYP3A4 inhibitors such as ketoconazole or clarithromycin. When the CYP3A4 inhibitor is
`
`withdrawn from the combination therapy, FANAPT dose should be increased to where it was
`before [see Drug Interactions (7.1)].
`Dosage adjustment for patients taking FANAPT who are poor metabolizers of CYP2D6:
`FANAPT dose should be reduced by one-half
`for poor metabolizers of CYP2D6
`Pharmacokinetics (12.3)].
`
`Hepatic Impairment: FANAPT is not recommended for patients with hepatic impairment.
`
`[see
`
`
`
`Reference ID: 2921042
`
`
`
`

`

`
`
`Maintenance Treatment
` 2.3
`
`Although there is no body of evidence available to answer the question of how long the patient
`treated with FANAPT should be maintained, it is generally recommended that responding patients
`be continued beyond the acute response. Patients should be periodically reassessed to determine
`the need for maintenance treatment.
`
`Reinitiation of Treatment in Patients Previously Discontinued
`2.4
`
`Although there are no data to specifically address re-initiation of treatment, it is recommended that
`the initiation titration schedule be followed whenever patients have had an interval off FANAPT of
`more than 3 days.
`
`Switching from Other Antipsychotics
`2.5
`
`There are no specific data to address how patients with schizophrenia can be switched from other
`antipsychotics to FANAPT or how FANAPT can be used concomitantly with other antipsychotics.
`
`Although immediate discontinuation of the previous antipsychotic treatment may be acceptable for
`some patients with schizophrenia, more gradual discontinuation may be most appropriate for
`others. In all cases, the period of overlapping antipsychotic administration should be minimized.
`
`DOSAGE FORMS AND STRENGTHS
`3
`FANAPT tablets are available in the following strengths: 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg and
`
`12 mg. The tablets are white, round, flat, beveled-edged and identified with a logo “
`”
`debossed on one side and tablet strength “1”, “2”, “4”, “6”, “8”, “10”, or “12” debossed on the other
`side.
`
`CONTRAINDICATIONS
`4
`FANAPT is contraindicated in individuals with a known hypersensitivity reaction to the product.
`Reactions have included pruritus and urticaria.
`
`
`
`
`5
`
`WARNINGS AND PRECAUTIONS
`
`Increased Risks in Elderly Patients with Dementia-Related Psychosis
`5.1
`Increased Mortality
`Elderly patients with dementia-related psychosis treated with atypical antipsychotic drugs
`are at an increased risk of death compared to placebo. FANAPT is not approved for the
`treatment of patients with dementia-related psychosis [see Boxed Warning].
`
`Cerebrovascular Adverse Events, Including Stroke
`In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly patients with
`dementia, there was a higher incidence of cerebrovascular adverse events (cerebrovascular
`
`Reference ID: 2921042
`
`
`
`

`

`
`
`accidents and transient ischemic attacks) including fatalities compared to placebo-treated patients.
`FANAPT is not approved for the treatment of patients with dementia-related psychosis [see Boxed
`Warning].
`
`
`
`QT Prolongation
` 5.2
`
`In an open-label QTc study in patients with schizophrenia or schizoaffective disorder (n=160),
`FANAPT was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice
`daily. The effect of FANAPT on the QT interval was augmented by the presence of CYP450 2D6
`
` or 3A4 metabolic inhibition (paroxetine 20 mg once daily and ketoconazole 200 mg twice daily,
`respectively). Under conditions of metabolic inhibition for both 2D6 and 3A4, FANAPT 12 mg twice
`daily was associated with a mean QTcF increase from baseline of about 19 msec.
`No cases of torsade de pointes or other severe cardiac arrhythmias were observed during the pre-
`marketing clinical program.
`The use of FANAPT should be avoided in combination with other drugs that are known to prolong
`
` QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol)
`thioridazine),
`antiarrhythmic medications, antipsychotic medications
`(e.g., chlorpromazine,
`antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the
`QTc interval (e.g., pentamidine, levomethadyl acetate, methadone). FANAPT should also be
`
`avoided in patients with congenital long QT syndrome and in patients with a history of cardiac
`arrhythmias.
`Certain circumstances may increase the risk of torsade de pointes and/or sudden death in
`association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2)
`hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc
`interval; and (4) presence of congenital prolongation of the QT interval; (5) recent acute myocardial
`infarction; and/or (6) uncompensated heart failure.
`Caution is warranted when prescribing FANAPT with drugs that inhibit FANAPT metabolism [see
`Drug Interaction (7.1)], and in patients with reduced activity of CYP2D6 [see Clinical Pharmacology
`(12.3)].
`It is recommended that patients being considered for FANAPT treatment who are at risk for
`significant electrolyte disturbances have baseline serum potassium and magnesium measurements
`with periodic monitoring. Hypokalemia (and/or hypomagnesemia) may increase the risk of QT
`prolongation and arrhythmia. FANAPT should be avoided in patients with histories of significant
`cardiovascular illness, e.g., QT prolongation, recent acute myocardial infarction, uncompensated
`heart failure, or cardiac arrhythmia. FANAPT should be discontinued in patients who are found to
`have persistent QTc measurements >500 ms.
`If patients taking FANAPT experience symptoms that could indicate the occurrence of cardiac
`
`arrhythmias, e.g., dizziness, palpitations, or syncope, the prescriber should initiate further
`evaluation, including cardiac monitoring.
`
`Neuroleptic Malignant Syndrome (NMS)
`5.3
`A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome
`(NMS) has been reported in association with administration of antipsychotic drugs. Clinical
`
`manifestations include hyperpyrexia, muscle rigidity, altered mental status (including catatonic
`
`Reference ID: 2921042
`
`
`
`

`

`
`
` signs) and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia,
`
`diaphoresis, and cardiac dysarrhythmia). Additional signs may
`include elevated creatine
`phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
`The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis,
`it is important to identify cases in which the clinical presentation includes both serious medical
`
` illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated
`extrapyramidal signs and symptoms (EPS). Other important considerations in the differential
`diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central
`nervous system (CNS) pathology.
`The management of this syndrome should include: (1) immediate discontinuation of the
`antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic
`
` treatment and medical monitoring, and (3) treatment of any concomitant serious medical problems
`
` for which specific treatments are available. There is no general agreement about specific
`pharmacological treatment regimens for NMS.
`If a patient requires antipsychotic drug treatment after recovery from NMS, the potential
`reintroduction of drug therapy should be carefully considered. The patient should be carefully
`monitored, since recurrences of NMS have been reported.
`
`Tardive Dyskinesia
`5.4
`Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic
`movements, which may develop in patients treated with antipsychotic drugs. Although the
`prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it
`
`is impossible to rely on prevalence estimates to predict, at the inception of antipsychotic treatment,
`
`which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in
`their potential to cause tardive dyskinesia is unknown.
`The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are
`believed to increase as the duration of treatment and the total cumulative dose of antipsychotic
`administered increases. However, the syndrome can develop, although much less commonly, after
`relatively brief treatment periods at low doses.
`There is no known treatment for established cases of tardive dyskinesia, although the syndrome
`
`may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment
`itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and
`thereby may possibly mask the underlying process. The effect that symptomatic suppression has
`upon the long-term course of the syndrome is unknown.
`Given these considerations, FANAPT should be prescribed in a manner that is most likely to
`
`minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally
`
`be reserved for patients who suffer from a chronic illness that (1) is known to respond to
`antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful
`treatments are not available or appropriate. In patients who do require chronic treatment, the
`smallest dose and the shortest duration of treatment producing a satisfactory clinical response
`should be sought. The need for continued treatment should be reassessed periodically.
`
`Reference ID: 2921042
`
`
`
`

`

`
`
`If signs and symptoms of tardive dyskinesia appear in a patient on FANAPT, drug discontinuation
`should be considered. However, some patients may require treatment with FANAPT despite the
`presence of the syndrome.
`
`Hyperglycemia and Diabetes Mellitus
`5.5
`
` Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or
`
` death, has been reported in patients treated with atypical antipsychotics including FANAPT.
`
` Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is
`complicated by the possibility of an increased background risk of diabetes mellitus in patients with
`
` schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given
`these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related
`adverse events is not completely understood. However, epidemiological studies suggest an
`
` increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with
`the atypical antipsychotics included in these studies. Because FANAPT was not marketed at the
`time these studies were performed, it is not known if FANAPT is associated with this increased
`risk. Precise risk estimates for hyperglycemia-related adverse events in patients treated with
`
`atypical antipsychotics are not available.
`Patients with an established diagnosis of diabetes mellitus who are started on atypical
`antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk
`factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment
`with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of
`treatment and periodically during treatment. Any patient treated with atypical antipsychotics should
`be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and
`weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical
`antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has
`resolved when the atypical antipsychotic was discontinued; however, some patients required
`continuation of antidiabetic treatment despite discontinuation of the suspect drug.
`
`Weight Gain
`5.6
`Based on the pooled data from the four placebo-controlled, 4- or 6-week, fixed- or flexible-dose
`studies, the proportions of patients having a weight gain of ≥ 7% body weight was 12% for
`FANAPT 10-16 mg/day, 18% for FANAPT 20-24 mg/day, and 13% for FANAPT (combined doses)
`versus 4% for placebo. The mean weight change from baseline to endpoint in the short-term
`studies was -0.1 kg for placebo versus 2.0 kg for FANAPT-treated patients. Across all short- and
`long-term studies, the overall mean change from baseline at endpoint was 2.1 kg.
`
`
`Seizures
`5.7
`In short-term placebo-controlled trials (4- to 6-weeks), seizures occurred in 0.1% (1/1344) of
`patients treated with FANAPT compared to 0.3% (2/587) on placebo. As with other antipsychotics,
`
`FANAPT should be used cautiously in patients with a history of seizures or with conditions that
`potentially lower the seizure threshold, e.g., Alzheimer’s dementia. Conditions that lower the
`seizure threshold may be more prevalent in a population of 65 years or older.
`
`Reference ID: 2921042
`
`
`
`

`

`
`
`
`
`5.8
`Orthostatic Hypotension and Syncope
`
`FANAPT can induce orthostatic hypotension associated with dizziness, tachycardia, and syncope.
`This reflects its alpha1-adrenergic antagonist properties. In double-blind placebo-controlled short-
`term studies, where the dose was increased slowly, as recommended above, syncope was
`
`reported in 0.4% (5/1344) of patients treated with FANAPT, compared with 0.2% (1/587) on
`placebo. Orthostatic hypotension was reported in 5% of patients given 20-24 mg/day, 3% of
`
`patients given 10-16 mg/day, and 1% of patients given placebo. More rapid titration would be
`expected to increase the rate of orthostatic hypotension and syncope.
`FANAPT should be used with caution in patients with known cardiovascular disease (e.g., heart
`
`failure, history of myocardial infarction, ischemia, or conduction abnormalities), cerebrovascular
`
`disease, or conditions that predispose the patient to hypotension (dehydration, hypovolemia, and
`treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be
`considered in patients who are vulnerable to hypotension.
`5.9
`Leukopenia, Neutropenia and Agranulocytosis
`
`
`In clinical trial and postmarketing experience, events of leukopenia/neutropenia have been
`reported temporally related to antipsychotic agents. Agranulocytosis (including fatal cases) has
`
`also been reported.
`Possible risk factors for leukopenia/neutropenia include preexisting low white blood cell count
`
`(WBC) and history of drug induced leukopenia/neutropenia. Patients with a pre-existing low WBC
`or a history of drug induced leukopenia/neutropenia should have their complete blood count (CBC)
`
`monitored frequently during the first few months of therapy and should discontinue FANAPT at the
`first sign of a decline in WBC in the absence of other causative factors.
`
`Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of
`infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia
`(absolute neutrophil count <1000/mm3) should discontinue FANAPT and have their WBC followed
`until recovery.
`
`
`Hyperprolactinemia
`5.10
`As with other drugs that antagonize dopamine D2 receptors, FANAPT elevates prolactin levels.
`Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin
`secretion. This, in turn, may inhibit reproductive function by impairing gonadalsteroidogenesis in
`both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have
`been reported with prolactin-elevating compounds. Long-standing hyperprolactinemia when
`associated with hypogonadism may lead to decreased bone density in both female and male
`patients.
`Tissue culture experiments indicate that approximately one-third of human breast cancers are
`prolactin-dependent in vitro, a factor of potential importance if the prescription of these drugs is
`contemplated in a patient with previously detected breast cancer. Mammary gland proliferative
`changes and increases in serum prolactin were seen in mice and rats treated with FANAPT [see
`
`Nonclinical Toxicology (13.1)]. Neither clinical studies nor epidemiologic studies conducted to date
`have shown an association between chronic administration of this class of drugs and
`
`Reference ID: 2921042
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`
`
`tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this
`time.
`In a short-term placebo-controlled trial (4-weeks), the mean change from baseline to endpoint in
`plasma prolactin levels for the FANAPT 24 mg/day-treated group was an increase of 2.6 ng/mL
`compared to a decrease of 6.3 ng/mL in the placebo-group. In this trial, elevated plasma prolactin
`levels were observed in 26% of adults treated with FANAPT compared to 12% in the placebo
`In the short-term trials, FANAPT was associated with modest levels of prolactin elevation
`group.
`
`compared to greater prolactin elevations observed with some other antipsychotic agents. In
`
`
`pooled analysis from clinical studies including longer term trials, in 3210 adults treated with
`iloperidone, gynecomastia was reported in 2 male subjects (0.1%) compared to 0% in placebo-
`treated patients, and galactorrhea was reported in 8 female subjects (0.2%) compared to 3 female
`
`subjects (0.5%) in placebo-treated patients.
`
`5.11 Body Temperature Regulation
`Disruption of the body’s ability to reduce core body temperature has been attributed to
`antipsychotic agents. Appropriate care is advised when prescribing FANAPT for patients who will
`be experiencing conditions which may contribute to an elevation in core body temperature, e.g.,
`exercising strenuously, exposure to extreme heat, receiving concomitant medication with
`anticholinergic activity, or being subject to dehydration.
`
`Dysphagia
`5.12
`Esophageal dysmotility and aspiration have been associated with antipsychotic drug use.
`Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular
`
`those with advanced Alzheimer’s dementia. FANAPT and other antipsychotic drugs should be used
`cautiously in patients at risk for aspiration pneumonia [see Boxed Warning].
`
`Suicide
`5.13
`The possibility of a suicide attempt is inherent in psychotic illness, and close supervision of high-
`risk patients should accompany drug therapy. Prescriptions for FANAPT should be written for the
`smallest quantity of tablets consistent with good patient management in order to reduce the risk of
`overdose.
`
`Priapism
`5.14
`Three cases of priapism were reported in the pre-marketing FANAPT program. Drugs with alpha-
`adrenergic blocking effects have been reported to induce priapism. FANAPT shares this
`
`pharmacologic activity. Severe priapism may require surgical intervention.
`
`Potential for Cognitive and Motor Impairment
`5.15
`FANAPT, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. In
`short-term, placebo-controlled trials, somnolence (including sedation) was reported in 11.9%
`
`(104/874) of adult patients treated with FANAPT at doses of 10 mg/day or greater versus 5.3%
`
`(31/587) treated with placebo. Patients should be cautioned about operating hazardous
`machinery, including automobiles, until they are reasonably certain that therapy with FANAPT does
`not affect them adversely.
`
`Reference ID: 2921042
`
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`

`
`
`ADVERSE REACTIONS
`6
`Clinical Studies Experience
`6.1
`
`Because clinical trials are conducted under widely varying conditions, adverse reaction rates
`observed in the clinical trial of a drug cannot be directly compared to rates in the clinical trials of
`another drug and may not reflect the rates observed in c